This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A. Specific Aims The aims of this COBRE project have been amended in response to recent changes in research focus and research progress, specific recommendations from the external advisory committee, and comments from Study Section reviews. To date this COBRE work has focused on age and diet induced leptin resistance, and the role that PTP1B plays in inducing leptin resistance within the hypothalamus. Though our work has established that hypothalamic PTP1B contributes to both age and diet-induced leptin resistance, the external advisory committee indicated that the narrow focus on PTP1B as the mechanism of leptin resistance was not likely to lead to significant funding. Therefore, we have revised the project, which now focuses on the contribution of altered leptin signaling in the hypothalamus and hippocampus to age-related declines in energy homeostasis and cognitive function, with a specific focus on the interaction between leptin and oxidative stress. This represents a novel research focus with substantial significance. The revised project lists four Specific Aims: Specific Aim 1: Test the hypothesis that aging enhances the negative effects of high fat diet (HFD) on brain leptin signaling, metabolism and behavior. Specific Aim 2: Test the hypothesis that aging will impair the ability of the animal to reduce body adiposity and recover normal brain leptin signaling following cessation of a HFD. Specific Aim 3: Test the hypothesis that leptin protects against oxidative stress in hypothalamic and hippocampal neurons by enhancing antioxidant enzyme activity via NRF2 signaling. Specific Aim 4: Determine the functional interaction between leptin signaling and oxidative stress within areas of the hippocampus and hypothalamus. It should be noted that while these Aims reflect a shift in focus based on previous aims, the overall scope of the project remains very similar. Namely, we continue to be interested in the role of leptin signaling in the regulation of energy homeostasis, and the negative impact that both aging and HFDs have on brain leptin signaling. The changes primarily reflect a shift away from a focus on PTP1B as a molecular mediator of leptin signaling, and more toward the impact of impaired leptin signaling on neuron function and the interaction of age-induced with age- and diet-induced oxidative stress.